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Clinical research

Delirium and epilepsy


Peter W. Kaplan, MB, BS, FRCP

S tates of altered consciousness such as delirium


and psychoses have long horrified humanity with the
specter of loss of an individual’s sovereignty and self-con-
trol, carrying with it the intimation of passage towards
death. Agitated states with altered awareness and com-
ponents of excitation and delusion have evoked the per-
ception of visitation by demons, spirits, or even divine
influence, but often with the consequence of ostracism
from society.This has led, even in an age of enlightenment,
to relegation to insane asylums. Only with Pinel and
Esquirol in France, Chiarugi in Italy, and in institutions
Delirium (a state of usually reversible global brain dys- such as Bethlehem (“Bedlam”) in England were there
function due to toxic, metabolic, or infectious causes) and organized societal efforts toward addressing such condi-
epilepsy (a condition of spontaneous, recurrent paroxys- tions of insanity as forms of illness, which were identifiable
mal electrical excitation or dysfunction) are becoming even if not successfully treatable.1 In the 20th century, sci-
increasingly better understood, and hence easier to diag- entific effort has been directed toward understanding
nose and treat. The clinical features of delirium predom- delirium and researching its causes.
inantly involve subacute changes in cognition, awareness, Epilepsy carried with it a similar societal view, also lead-
and activity levels, behavioral disturbance, clouding of ing to incarceration and often draconian remedies. These
consciousness, and sleep–wake cycle changes. In contrast, conditions often are intertwined in terms of both clinical
epilepsy involves the acute interruption of brain function, features and common substrates and triggers. A clearer
often with convulsive activity, falls, and injury. States that distinction has been drawn between the two only by close
may share the clinical features of both, such as noncon- clinical observation of phenomenology and, in the 20th
vulsive epileptic states, are also important: the cause of century, by electroencephalography (EEG), enabling an
brain derangement is one of excessive and abnormal elec- electrophysiologic differentiation between them. But still
trical brain activity. In such conditions, the clinical mani- they merge, as will be described.
festations may resemble states of delirium and confusion, The term epilepsy, derived from the Greek epilambanein,
and the absence of convulsive clinical activity is significant. arose from the concept that the individual was “seized,”
Electroencephalography remains the diagnostic test of
choice: it is essential for differentiating these two condi- Keywords: delirium; epilepsy; pathogenesis; ictal, interictal, and postictal deli-
rium; EEG; nonconvulsive status epilepticus
tions, enabling the distinctly different treatments for delir-
ium and epilepsy. Ongoing research and investigation are Author affiliations: Johns Hopkins Bayview Medical Center, Department of
Neurology, Baltimore, Md, USA
essential to better understand the abnormal brain mech-
anisms underlying delirium, and to develop better tools Address for correspondence: Peter W. Kaplan, MB, BS, FRCP, Johns Hopkins
Bayview Medical Center, B Bldg, 1 North, Room 125, 4940 Eastern
for objective diagnosis. Avenue, Baltimore, MD 21224, USA
Dialogues Clin Neurosci. 2003;5:187-200.
(e-mail: pkaplan@jhmi.edu)

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Clinical research
Selected abbreviations and acronyms Even as far back as 1808, an epileptic murderer was
acquitted on the basis of diminished responsibility and
ASE absence status epilepticus placed in a workhouse. Falret, in France, described deliri-
CPSE complex partial status epilepticus ous types that could either precede or follow convulsive
GABA -aminobutyric acid attacks. Such an “epileptic delirium” was seen in patients
NCSE nonconvulsive status epilepticus without acute convulsions. It “substituted” for the epilep-
REM rapid eye movement tic convulsions and was viewed as another manifestation
of the same disease, but in a different form.9 Delirium in
gripped, or attacked by forces, thus presupposing a rela- this sense, represented “larval or masked epilepsy.” Samt,
tively circumscribed duration; while delirium comes from in Germany, described patients “characterized by violence,
the Latin for “to leave the furrow,” representing a “leave- fits and religious ecstasy.”10 Such prophesying epileptics
taking” of one’s senses. had seizures followed by a state of mental twilight and
Descriptions of such illnesses occur in ancient texts, with confusion:
early accounts of delirium delineated as a mental disor-
der, and can be regarded as a model of physicians’ efforts One patient before or after seizures, fell into an irritated and
at understanding the diseased mind.2,3 Hippocrates in his excited state, condemned his godless environment, mistook
book Epidemics describes a condition characterized by others for devils, thrashed, and wished to be crucified for
restlessness, shifting moods, and visual hallucinations at the faith.
night, but with lucid intervals.4 Studies by Esquirol
described maniacal attacks or furor epilepticus in which As noted by Krafft-Ebing11 :
“raving fits” of lunatics were associated with epileptic
symptoms.5 Such observations were made by Tyson Consciousness is considerably dim during this delirious
(1650-1708) as a physician to the Bethlehem Hospital.6 state, but still amenable to impressions from the external
Prichard went on to describe7: world.Accordingly, there does not exist any defective mem-
ory afterwards. The patient remembers his divine visions
The face is flushed, and the aspect of the patient is like that and does not correct them.
of a man under intoxication; he attempts to start from bed
and run about and, on being withheld, reciprocates and Introduction
endeavors to overcome resistance. Sometimes an appear-
ance of maniacal hallucination displays itself, but more In brief, contemporary neurobiological understanding of
generally the disorder resembles frenetic delirium. It com- delirium attributes it to a derangement in the correct func-
monly continues 1, 2, or 3 days, during which the patient tioning of cortical neuronal communication, largely caused
requires confinement in a strait waistcoat, and then grad- by toxic influences of exogenous and endogenous sub-
ually subsides, and the patient returns into his previous stances. This is often consequent to internal organ dys-
state. function with toxic-metabolic effects on the neuronal sub-
strates subserving the correct balance of pathways that
At the end of the 18th century, Foderé described a “peri- support cognition, memory, and arousal. It is a perturba-
odic delirium” that probably included cases of epileptic tion of the mind, as much as of the brain.
mania8: Epilepsy, in contrast, is more of an acute and spontaneous,
largely unpredictable, paroxysmal dysfunction of some, or
These paroxysmals do not come on suddenly. Usually the most, of the brain functions, with a highly variable impact
patient feels their approach; they are preceded by a noise in on subjective sensory perception, motor control, and—at
the head and frightening dreams; then the patient feels its worst—consciousness and vital centers. With convul-
something ascending from the lower parts of the body to sive excitation of motor pathways, this leads to postictal
the uppermost, almost as in the aura epileptica. He loses exhaustion and variable unconsciousness. In almost all
consciousness; he falls down; he is raised up again and is cases, this has been identified as being due to hyper-
now raging. excitable and chaotic neuronal brain discharges, express-
ing themselves clinically, as an excited “exaggeration” of

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Delirium and epilepsy - Kaplan Dialogues in Clinical Neuroscience - Vol 5 . No. 2 . 2003

the function of the part of the brain affected. In effect, Clinical features of delirium
epileptic excitation of a particular brain region, such as
motor cortex, would lead to contralateral limb or axial Delirium is the most frequently seen mental dysfunction
movement represented by that cortex. As an example, in the critically ill.14 Particularly prevalent in the elderly,
chaotic neuronal bursts in the temporal lobe could lead to it can be seen about 20% of hospitalized patients15,16 as
memory evocation of distant, isolated perceptions, and described by Lipowski17:
memories. This excitation has been delineated at the cel-
lular and tissue levels by recording cellular discharges in Delirium is a transient organic mental syndrome of acute
vitro in brain slices, while noninvasive diagnostic EEG can onset, characterized by global impairment of cognitive
record such synchronous discharges at the scalp surface in functions, reduced level of consciousness, attentional
animals, and in humans affected with epilepsy. abnormalities, increased or decreased psychomotor func-
Differentiation among delirium, dementia, psychosis, and tion, and a disordered sleep–wake cycle.
seizures can sometimes be difficult, given the shared clini-
cal features of many of these disorders. This article will The clinical features of delirium predominantly involve
include discussion of the pathophysiology and clinical fea- impairment of cognition and awareness. Motor activity
tures of delirium and epilepsy, provide indices for their diag- may be decreased or increased, but it often is character-
nosis, and discuss the differentiating, as well as overlapping, ized by agitation with behavioral disturbance. The cloud-
features of seizures and delirium. It will also discuss transi- ing of consciousness typically impairs insight and a
tions between the two, the role of medications and toxic change in outlook, bringing the patient to medical atten-
influences, the ambiguity of EEG, and the concept of an tion. There is impaired orientation to time, place, and
ictal delirium, combining the elements of both states. occasionally person, with the patient appearing to wan-
der in space and time (usually in the past), confusing
Definition and diagnosis even close family members, the unfamiliar hospital sur-
roundings, the seasons, and years. Nocturnal–diurnal
The Diagnostic and Statistical Manual of Mental Disorders, sleep–wake cycles are often impaired and may be
Third Edition, Revised (DSM-III-R) distinguishes between inverted, with sundowning characterized by agitation at
organic mental disorders and organic brain syndromes.12 the day’s end, but lethargy or sleep during the daylight
The criteria for organic brain syndromes do not refer to hours. It may engender lethargy or passivity with
etiology, while those for organic mental disorders do. decreased eating and responsiveness during the day,
Delirium refers to transient “clouding of consciousness” alternating with agitation, anxiety, hallucinations, and
with fluctuating attention, disordered thinking, and several hyperphasia at night. Any particular patient may have
other abnormal behaviors. One caveat in evaluating the one or more of these disturbances, but the individual
literature relating delirium, psychosis, and epilepsy has patient may have a highly variable temporal course and
been the broad inclusion of delirious and manic states manifestations of these features. Physicians on their brief
under psychosis by some authors. Many do not define their rounds may fail to note the fluctuating mental status so
inclusion criteria, and terminology varies from culture to characteristic of delirium, while the nursing staff with a
culture. In the Diagnostic and Statistical Manual of Mental more prolonged observation bring the key signs to clini-
Disorders, Fourth Edition (DSM-IV), postictal confusion cal attention.18
or delirium is not included under psychosis, but there are Delirium may be differentiated into two forms.18,19 The
strong resemblances with the similarity of symptoms, first type is characterized by excitation, anxiety, anger,
behavioral aberration, and confusion.13 and changes in behavior with hypervigilance and typi-
Neurologists and psychiatrists often disagree on termi- cally signs of autonomic excess. This type follows ben-
nology: some authorities refer to a euphoric confusional zodiazepine, alcohol, or barbiturate withdrawal, or the
state with hypervigilance and hyperactivity as delirium, use of central nervous system–stimulating drugs such as
while others refer to lethargy and psychomotor slowing in cocaine or amphetamines. A second type is character-
confusional states. Delirium tremens is characterized by ized by psychomotor retardation, indifference and apa-
hyperactivity and hypervigilance with EEG showing thy, impaired cognition, and physical activity with a
sparse normal alpha, but increased beta activity. decreased level of consciousness. The distinction may not

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Clinical research
be clear, and one state may give way to the other, for Pathogenesis
example, following a period of excitation with alcohol
withdrawal, a patient may pass over into a state of A number of causes for delirium have been identified
obtundation and lethargy. (Table I). Risk factors include prior cognitive impairment,
advanced age, intercurrent infection, bone fracture, and
Higher cortical function medication use, particularly narcotics and neuroleptics.
Postanesthesia delirium is common.25 Nonetheless, many
Delirium is characterized by impairment of higher cor- delirious patients have no clear toxic or metabolic abnor-
tical functions, involving defective thinking, memory, and mality. Some have attributed these states to environmen-
spatial, temporal, and personal orientation. The imme- tal changes, particularly in the demented and elderly.
diate environment may be misinterpreted or appear There are a number of mechanisms that may disrupt
abnormal (illusions), and sights, sounds, or sensory stim- sleep–wake cycles and cognition.Arousal and cortical acti-
uli may be perceived when not truly present (hallucina- vation involves the ascending reticular activation system
tions); auditory hallucinations with voices, however, (ARAS), which modulates cortical excitability and wake-
would suggest a psychosis rather than delirium.3 Patients fulness. Electrical stimulation of the ARAS may induce
appear incoherent, unable to direct and sustain lines of behavioral arousal in sleeping animals.26 Conversely, lesions
thought, and unable to understand abstract ideas and of the reticular system can induce a sleep-like state.3,27 From
use appropriate judgment. Learning, retention, and such experiments, it appears that both sleep and coma are
recall may be impaired with consequences on recent and consequent to decreased inflow of tonic ascending impulses
long-term memory. There may be confabulation and subserving wakefulness. A number of neurotransmitters
emotional lability. Patients are easily distractible and have been suggested to be involved in this process.28-32
cannot sustain directed mental efforts. Tasks are left Serotonergic input modulates slow-wave sleep and initiates
unfinished, and there may be perseveration in thoughts, rapid eye movement (REM) sleep. The serotonergic and
speech, and action. catecholaminergic systems can also act antagonistically to
produce wakefulness and slow-wave sleep alternately, but
Behavioral problems both induce REM sleep.30 A highly complex but coordi-
nated neocortical structure is “aroused” to consciousness
Hyperactive delirium frequently manifests as anxiety, by local circuit neurons, projections from ipsilateral and
agitation, or even anger.18-21 At the other end of the spec- contralateral hemispheres, as well as by deeper structures
trum, lethargy, somnolence, or even catatonia may occur. in the pons and thalamus, and in basal forebrain.3
Patients may exhibit both ends of the spectrum. Limbs Impairment of the integrity of this anatomical system
or facial jerks, tremors, and voluntary or involuntary (which is essential for self-awareness) can reduce attention
limb and face movements can occur with fluctuating and disrupt sleep or wakefulness.
intensity, making it difficult to differentiate from non- In addition to the cholinergic hypothesis of delirium,
convulsive status epilepticus (NCSE). It is the hypoac- which is supported by the observation that anticholiner-
tive patient whose diagnosis may be overlooked. gic drugs frequently cause delirium, is the observation that
delirium can be relieved by dopamine blockade.
Prognosis Observations of this reciprocal relationship between
cholinergic and dopaminergic brain effects indicate a role
Delirium is usually considered to be a transient disor- for dopaminergic excess in delirium. The delirium associ-
der of the mind, but it typically appears in the setting ated with bupropion toxicity has been postulated to be
of more serious underlying dysfunction. The morbidity due to excessive dopaminergic activity.33 Delirium may
and mortality, therefore, stem more from the underly- also occur from serotonergic intoxication seen with sero-
ing conditions engendering delirium, rather than from tonin syndrome,34 resulting from concomitant use of sero-
the delirium itself. Mortality appears to range from a tonergic agents. Decreased γ-aminobutyric acid (GABA)
quarter to a third of patients, whether assessed at the activity has been implicated in delirium from sedative
time of admission or over 3 or 6 months from diagno- drug withdrawal, or toxic ictal delirium.35 It has been sug-
sis.22-24 gested that, since the thalamus is rich in GABA, reduc-

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tions in GABA affect thalamic gating stimuli. Similarly, even visual illusions, but few behavioral changes.38,39 It has
antibiotics may induce delirium by reducing activity at the been postulated, therefore, that disruption of sleep–wake
GABA receptors. More recent research has also centered cycles might, in turn, result in the inappropriate intrusion
on the role of glutamate, β-endorphin, and glucocorticoids of elements of sleep and dreaming into wakefulness, or
in delirium, but further clarification is needed. other waking state during sleep.40 It is not clear, however,
Strikingly, many of the symptoms of delirium resemble that sleep deprivation per se is an intrinsic trigger of delir-
abnormal dream states, and experimental efforts have ium in hospitalized patients. It has been postulated that
been directed at inducing delirium through manipulation sensory deprivation alone, or on impaired brain home-
of the sleep–wake cycle. Sleep-deprived volunteers can ostasis, such as with dementia or diffuse atrophy, may
have visual and auditory hallucinations, as well as delu- engender delirium. However, even in normal subjects, sen-
sions, with poor cognition.36,37 REM deprivation can induce sory deprivation can result in visual illusions, but without
fatigue, irritability, depersonalization, disorientation, and delirium. It has long been observed that patients in rooms

Central nervous system Systemic disease


Trauma Noncerebral nervous system disease
Closed head injury/concussion • Metabolic/electrolytes
Contusion • ↑Na; ↓Na
Epidural, subdural, and intracerebral hemorrhage • ↑Glucose; ↓glucose
• ↑Ca; ↓Ca
• ↑CO2; ↓O2
Cerebrovascular compromise Systemic failure
• Transient ischemia: nondominant; thalamic: brain stem • Hepatic
• Infarction: large hemisphere, thalamic; hematomas • Renal
• Hemorrhage: subarachnoid or intracerebral • Pulmonary
• Cardiac
• Endocrine
• Hypothyroidism
Hypoparathyroidism/hyperparathyroidism
Hypocortisolemia/hypercortisolemia
Seizures/ictal states Infection
Nonconvulsive states • Systemic
• Complex partial status epilepticus • Organ
• Absence status epilepticus • Lung
• Postictal confusion • Kidney or urinary tract
• Paroxysmal lateralized epileptiform discharges (PLEDs) Fever
• Ictal encephalopathies (eg, intoxication with Drugs, medication
lithium, tiagabine) Drug abuse/alcohol
Drug withdrawal
Hypertensive encephalopathy/hypotension
Paraneoplastic states
Neoplasia Immunological/endocrine dysfunction
• Primary brain tumors • Hashimoto’s encephalopathy
• Metastases • Thyroid storm
• Carcinoma
Infection
• Meningitis
• Encephalitis

Table I. Causes of delirium.

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in surgical intensive care units without windows have a and inattention.Also, delirium has a more acute onset and
higher incidence of postoperative delirium.41 greater fluctuation than simple dementia. Some fluctua-
Other frequent causes include drug and alcohol with- tion occurs in dementia, and delirium can appear in the
drawal syndromes, probably representing the removal setting of a chronic dementing process.55 In psychosis,
of depressant effects on downregulated systems, with severe cognitive defects are rare, while auditory halluci-
rebound hyperexcitability.A REM-sleep rebound may fol- nations are elaborate and frequent, and the EEG is nor-
low drug withdrawal, intruding into waking states in the mal.56 Olfactory hallucinations, however, may be mistaken
form of hallucinations, delusions, and psychotic phenom- for epileptic aurae.As noted before, in delirium, cognitive
ena.3,42,43 Other pathophysiological explanations include deficits are marked with poorly organized and variable
decreased acetylcholine synthesis21,44 and stress-induced visual hallucinations.The EEG usually shows diffuse back-
augmentation of cortisol.45,46 In hepatic and renal suffi- ground slowing or intrusion of slower frequencies. Early
ciency, there may be abnormal elaboration of neurotrans- studies by Engel and Romano correlated clinical, psycho-
mitter substances that unbalance pathways subserving logical, and EEG slowing in delirium, linking increasing
arousal and cognition, thus impairing sleep–wake cycles lethargy with EEG desynchronization.57,58 Progressive
and normal cerebral processing.47-49 Even in normal sub- impairment in the Mini-Mental Cognitive Scores also cor-
jects, anticholinergic medications may produce delirium, relates with slowing on EEG.59 Conversely, with delirium
disordered attention, impaired abstract thinking, tempo- following drug withdrawal, the EEG may show fast activ-
ral perception, and impaired memory.50,51 The interplay ity. Many of the typical differentiating features among psy-
among serotonergic, cholinergic, and noradrenergic mech- chosis, drug withdrawal, and delirium have been elabo-
anisms may thus be disrupted to impair the cognitive and rated on by Lipowski.3,60-62 Some investigators have
arousal functions of the brain.3 reported intermittent bursts of bitemporal sharp activity
There is increasing information to suggest that the neu- on EEG in patients with rapid mood swings, psychotic
ronal dysfunction leading to delirium may occur from episodes, depression, rage attacks, and suicide attempts,63
more focal cortical, subcortical, or combined dysfunction. as well as in bipolar disorders and rapid mood cycling.64
Geschwind has suggested that focal lesions, for example, Problems of differentiating delirium and seizures can stem
of the right hemisphere, may impair attention.52 Evidence from the paroxysmal nature of the altered mental status
for this has come from structural and functional brain- and behavior that can occur with delirium, which may be
imaging techniques, as well as from brain-lesion patients. mistaken for the confusion and agitation of complex par-
Areas implicated include the caudate, and wider basal gan- tial seizures, postictal states of confusion, or even NCSE.
glial involvement, right subcortical strokes, right perime- A frequent presentation of delirium is in the elderly
dian thalamic stroke, and stroke of the left caudate or right patient in the postoperative period, who appears feverish,
frontal cortex all indicate the involvement of thalamus and agitated with sleep–wake cycle inversions, hallucinosis, and
frontal regions in delirium.53 confusion. Here, there can be interplay of multiple organ
system impairments or failures, including renal, hepatic,
Differential diagnosis cardiac, respiratory, or endocrine.65-69 Even when correctly
identified, delirium may carry a high morbidity and mor-
Although delirium is frequently overlooked or misdiag- tality, but when misidentified as psychosis, seizure, or
nosed,54 confusion is often the first sign to be noted, fol- attributed to a dementing process, there may be inappro-
lowed by waxing and waning cognitive function, incoher- priate management. An agitated, confused, and uncoop-
ence, and an inversion of sleep–wake cycles. Once delirium erative patient presents major management, and diagnos-
has been identified, investigation is directed at underlying tic dilemmas to nursing and medical staff.
causes (Table I).When hallucinations and agitation appear,
but alertness and memory are relatively preserved, then a Seizures and delirium
psychosis or drug-induced psychiatric condition may be
present. Delirium can be accompanied by overactivity of It may be often difficult to differentiate ictal from a deliri-
the autonomic system, producing sweating, pupil dilata- ous cause of agitation and altered mental status, particu-
tion, and tremor. Dementia usually occurs in a clear sen- larly in psychiatric patients who are prone to both seizures
sorium, without autonomic dysfunction, a little drowsiness, and delirium, let alone psychosis.70-77 An early delineation

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of a personality type, the so-called “temporal lobe person- and 50 min after a single seizure in up to three-quarters of
ality,”78,79 underlies the concept of temporal-limbic abnor- cases following temporal lobe seizures, and in slightly
mality that may lead to either psychosis or epilepsy.80 The fewer after seizures with a frontal lobe origin.88
older literature describes an “epileptic delirium,” which is In the postictal or interictal periods, there may occasion-
characterized by hallucinations and delusions, a diminished ally be acute psychosis in subjects without a prior psychi-
level of consciousness, and a confusional state.75 In the atric history. Such released automatisms may also engen-
patient who may be delusional, agitated, or hypermanic, der bizarre movements or behavior. Left-sided foci have
Landoldt described epileptiform discharges on the EEG been associated with dysphoria, while right-sided dis-
with alternating dysphoria and psychosis.81 Directed vio- charges have been seen with laughter and hypomania.89
lence in the context of an epileptic “delirium” has been Occasionally, with a relatively normal EEG, a postictal
used as an “epilepsy defense” in patients accused of violent delirium can be seen after a flurry of seizures.78 However,
crimes, but a study by Treiman revealed little evidence of in most patients, psychosis is a postictal phenomenon
increased violence among people with epilepsy compared (Table II).90
with the general population.82 Violent behavior in this set-
ting is usually of a “resistive” character with the confused Interictal and preictal delirium
patient trying to break away from physical restraint.
Among the different seizure types that may present with As noted, components of delirium can be seen in the
confusional states, those of complex partial seizures, period between seizures, and also before seizures.78,80,91,92
whether repeated or prolonged, can result in marked agi- Some patients with a delirious encephalopathy have
tation, at times with hypomania, hallucinations, illusions, EEGs showing profuse, bilateral, synchronous spike, and
and religiosity.35,83-87 These rarely occur as the initial or slow-wave discharges.35 Such discharges may at times
heralding event of epilepsy, and there is almost invariably resemble triphasic waves, particularly in the setting of a
prior history of epilepsy. During the event, diagnosis can- metabolic or toxic encephalopathy. Causes include raised
not be made without observation of ongoing, usually lat- ammonia, lithium, tricyclic antidepressant toxicity,
eralized, epileptiform activity on the EEG with waxing tiagabine treatment, baclofen, metrizamide, ifosfamide,
and waning patterns, and discharge frequency usually and other medications.93 These patterns may be indistin-
exceeding one per second. After isolated complex partial guishable from the EEG perspective, from NCSE. In such
seizures, there may be a rise in prolactin level between 20 cases, the EEG may normalize or at least show marked
reduction in epileptiform morphologies, but the patient
• Psychotic or other psychiatric symptoms appear within at may remain clinically encephalopathic.93 In other cases,
least 7 days after a lucid interval following a seizure or, both an epileptic and a triphasic encephalopathic state
more commonly, a series of seizures may coexist. One such case with raised ammonia and flur-
• The event may be characterized by psychosis, depression, ries of epileptiform triphasic waves showed resolution of
elation, or anxiety-related symptoms this EEG activity following benzodiazepines, with a grad-
• The event is not simply an extension of the patient’s previ- ual normalization and improvement in state of conscious-
ous mood or mental state prior to the onset of the ness over 12 h, but a further rise in serum ammonia.94
seizure(s)
• The event is usually limited to days, rarely weeks Ictal delirium
• The patient does not have significant clouding of con-
sciousness as in delirium, and confusion—when present— The transient encephalopathies or cortical impairment
can be attributed to the psychiatric symptoms (especially seen after seizures usually resolves over minutes to hours,
psychosis) although on some occasions, this may take days. Biton et
• The event cannot be attributed to other medical or other al, however, have identified a more prolonged postictal
psychiatric causes (eg, drug intoxication, metabolic distur- encephalopathy lasting for 4 to 10 days after a cluster of
bances, head injury, or complex partial status) seizures.84 In this case, the EEG pattern was irregular in
Table II. Criteria for postictal psychiatric disturbances. patients with borderline or mild mental retardation.
Adapted from reference 91: Logsdail SJ, Toone BK. Post-ictal psychoses: a clinical and
phenomenological description. Br J Psychiatry. 1988;152:246-252. Copyright © 1988,
In patients with prior structural abnormalities, such as
The Royal College of Psychiatrists. strokes, there may be periods of diminished level of con-

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Clinical research
sciousness and abnormal behavior in association with an gested that, with limb movements, adversive gaze devia-
EEG pattern of periodic lateralized epileptiform dis- tion, nystagmus, or documentation of increased cerebral
charges (PLEDs).91 Such borderline states between intraic- flow or metabolism using single photon emission com-
tal “irritability” around an epileptogenic zone can result in puted tomography (SPECT), positron emission tomogra-
pseudoperiodic lateralized discharges varying from one phy (PET), or perfusion weighted magnetic resonance
every 5 to 10 seconds, through the entire range to more imaging (MRI), an ictal state is present.95 Such differenti-
than one per second. It becomes exceedingly difficult to ation has led to recommendations of more aggressive sup-
decide whether such a state is representative of an inter- pression of seizures in the form of status epilepticus on the
ictal state, cortical irritability, or an ongoing status epilep- assumption that there was a danger of ongoing neuronal
ticus. The cutoff has long been somewhat arbitrary at exhaustion and added brain insult.82 This finding and con-
between 0.5 and 1.5 Hz, but more recent studies have sug- clusion have not been supported by other investigators.

ASE CPSE
Attitude Unreactivity to threat Anxious
Lack of initiative Aggressive
Inability to plan Irritable
Withdrawal
Affect Indifference Fearful
Perplexity “Ironic” appearance
Crying “Puzzled”
Laughing Smiling
Aggressivity
Memory/cognition Variable amnesia Diminished consciousness
Slow ideation Confabulation
Disorientation Amnesia
Disorientation
Speech Verbal perseveration Verbal automatisms
Monosyllabic answers Speech arrest
Lack of spontaneous speech Mumbling
Interrupted speech Aphasia
Clicking noises in mouth Abnormal vocalizations
Mutism
Humming
Motor Hippus Complex motor automatisms
Clumsy motor performance Oroalimentary automatisms
Motor perseveration Motionless staring
Automatisms (chewing; Perseverative gesticulations
compulsive handling of objects) Head and eye deviation/nystagmus
Rhythmic blinking Limb extension
Eye rolling Blinking
Small amplitude jerking of face or arms Myoclonic jerks of face, mouth and limbs
Quivering of lips
Tonic neck spasms
Ataxic gait/pseudoataxia
Wandering
Table III. Clinical features of nonconvulsive status epilepticus (NCSE): differentiation between absence status epilepticus (ASE)98 and complex partial sta-
tus epilepticus (CPSE) (presented at the ECNS Meeting; Baltimore, Md; September 2002).
Continued on page 195

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NCSE also presents in various forms as a delirious state. vulsive states are given in Table IV.97 The cardinal features
It has been traditionally classified into (i) absence status of ASE may be only mild obtundation, withdrawal, and
epilepticus (ASE); and (ii) a lateralization-related NCSE confusion, but there is often paucity of speech with halting
complex partial status epilepticus (CPSE), which has, in monosyllabic answers, variable amnesia, but frequent eye-
turn, been further subdivided into frontal and temporal lid, perioral, and limb myoclonia. The patient may com-
subtypes.96 Each of these varieties has somewhat different plain of visual hallucinations or go into a dreamy state and
behavioral aspects, although there is overlap among the interact in a vague and inappropriate manner.101 Patients
different types.97 A classification of NCSE in terms of ASE appear disoriented and quiet, and give a description of
and CPSE is given in Table III.98 NCSE is one of the great “closeness” or “heat.” The patient may present with hos-
imitators and the only way to differentiate these ictal states tility and aggression, agitation, and impulsive behavior.102,103
from types of encephalopathy and delirium of nonictal Of particular interest has been the recent delineation of
cause, is an EEG. These ictal states are more frequently CPSE into frontal lobe subtypes. Recent work by Thomas
seen in particular settings, as noted in Table III. Some gen- et al elucidated a more frequent variety characterized by
eral distinctions can be made between ASE and CPSE. affective disinhibition, indifference, and mood disturbances
For example, anxiety, aggression, fear, and irritability are with subtle impairment of cognitive functions associated
more frequently seen with CPSE than with ASE, as are with unilateral frontal seizure activity (type 1), while there
stereotyped automatisms.97 Eye deviation, nystagmus, and was a less frequent variety (type 2) with bilateral, asym-
lateralized automatisms are also seen with CPSE. With metric frontal foci and more marked behavioral distur-
both types, however, agitation, aggressivity, violent behav- bances, temporospatial disorientation, confusion, and per-
ior, and hallucinations occur.99,100 Some of the striking severation.104 These recent descriptions have highlighted
behavioral/delirious manifestations seen in these noncon- the fact that nonconvulsive states are characterized less by

ASE CPSE
Behavior Inappropriate for situation with Wandering
preserved alertness Violent behavior
Infantile behavior Agitated unresponsiveness
Fugue states Psychotic behavior
Catatonia
Psychiatric Hallucinations
Paranoid persecution
Experiential Feeling of oppression Visual “bright spots”/dancing colors
Uncontrollable rush of thoughts “Structures that change shape”
Desire to (but inability to) perform Movement
simple motor acts (motor apraxias) Paranoia
Dreamy state: “feels vague” Déjà vu
“In a different world”
“Drifting away”
“Drunk”
Worried; edgy
Dizzy
Missing pieces of conversation
Central vision “vibrates”
Other Incontinence
Diarrhea
Headache
Frontal release signs
Babinski reflex
Table III. Continued.

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Clinical research
“a confusional state” than by a “mood disturbance,” where activity regressed during this psychotic period.106 It has
affective disinhibition, hypomania, and fear predominate long been noted that there is a reciprocal relationship
over significant obtundation. The behavioral aspects of between epilepsy control and abnormal psychiatric states,
NCSE have been extensively reviewed recently.98 which led to the treatment of schizophrenia by electro-
ASE and CPSE may present as a delirious state, and may convulsive therapy. Some patients with paradoxical nor-
be overlooked unless an EEG is obtained. However, in malization have anxiety, insomnia, and social inversion.
other wandering states with amnesia, the EEG may be Patients with a clinical diagnosis of psychosis have occa-
unrevealing. Episodes of confusion with amnesia although sionally been found to have pure unilateral limbic status
without dissociative features can occur with NCSE. epilepticus,107 as may patients with ASE.108 Patients report
Typically, though, automatisms, muscle twitching, confu- hallucinations, intense panic, apathy, anxiety, delusions, and
sion, and waxing and waning verbal responsiveness are a change in personality. A series of 52 cases of “epileptic
noted. clouded states” were described by Levin.109 Logsdail and
Some authors describe classic mania of limited duration in Toone established criteria for postictal psychosis, includ-
the postictal period. Such patients had right temporal lobe ing a clouding of consciousness and delirium with disori-
foci. entation, hallucinations, and delusions, but a clear senso-
Perez and Trimble105 noted that 50% of patients with psy- rium, lasting up to 3 months.90 This may occur shortly after
chosis and epilepsy were diagnosed as having schizophre- a seizure, or after a return to normal mental status. One
nia. One report by Dongier et al found that of 516 patients, case report by So et al demonstrated that postictal psy-
12.8% had ASE, 24.4% had slow delta activity with con- chosis is not necessarily an “epileptic equivalent” of the
fusion, and 24.4% had forced normalization; epileptiform limbic system.110 During an admission for epilepsy surgery,

Percentage of affected cases


ASE/AASE TCPSE FCPSE
Cognition
Impaired consciousness ≥90% 51% to 90% 51% to 90%
Fluctuating level of consciousness ≥90% 26% to 50% 26% to 50%
Slowness 26% to 50% <10% 26% to 50%
Verbal automatisms <10% 11% to 25% <10%
Confabulation <10% <10% 11% to 25%
Paranoia <10% 26% to 50% <10%
Mood
Indifferent; brooding 11% to 25% <10% 11% to 25%
Puzzled; mute 11% to 25% <10% 26% to 50%
Ironic <10% <10% 26% to 50%
Smiling; laughing <10% <10% 26% to 50%
Anxious; frightened <10% 26% to 50% <10%
Angry <10% 11% to 25% <10%
Aggressive; irritable 51% to 90%
Agitated 11% to 25% <10% <10%
Movements
Simple automatisms 11% to 25%
Complex automatisms <10% 26% to 50% <10%
Wandering <10% 11% to 25% <10%
Facial/global myoclonia 50% to 90% <10% <10%

Table IV. Behavioral distinctions between absence status epilepticus (ASE), atypical absence status epilepticus (AASE), temporal lobe complex partial
status epilepticus (TCPSE), and frontal lobe complex partial status epilepticus (FCPSE).
Adapted from reference 97: Rohr-le-Floch J, Gauthier G, Beaumanoir A. Etats confusionelles d'origine épileptique: interêt de l’EEG fait en urgence. Rev Neurol (Paris). 1988;144:425-436.
Copyright © 1988, Masson, Paris, France.

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Delirium and epilepsy - Kaplan Dialogues in Clinical Neuroscience - Vol 5 . No. 2 . 2003

• Lethargy and confusion attributed to a postictal state tal delirium. Many of the conditions resulting in delirium
• Ictal confusion mistaken for metabolic encephalopathy may also induce seizures, including hepatic and renal fail-
• Unresponsiveness and catalepsy presumed to be ure, electrolyte and metabolic abnormalities, drug intoxi-
psychogenic cations, intracranial infections, and occasionally lateralized
• Obtundation thought to be due to alcohol or drug intoxi- acute cerebrovascular events. In some overtreated patients
cation with epilepsy, there may be intoxication with anticonvul-
• Hallucinations and agitation mistaken for psychosis or sants and delirium. Other patients may have both delirium
delirium and epilepsy. Moreover, borderline states between the two
• Lethargy presumed secondary to hyperglycemia have been delineated. There is an increasing understand-
• Mutism attributed to aphasia ing of the different nonconvulsive states and borderline
• Laughing and crying ascribed to emotional lability ictal states that continue to evade diagnosis and appropri-
Table V. Clinical examples in which the diagnosis of nonconvulsive status ate treatment in the absence of an EEG.
epilepticus (NCSE) was missed or delayed according to experi- Some broad differences, albeit with exceptions, can be
ence at Johns Hopkins Bayview Medical Center, Baltimore, Md.
Adapted from reference 98: Kaplan PW. Behavioral manifestations of nonconvulsive noted. Delirium typically begins more gradually and per-
status epilepticus. Epilepsy Behav. 2002;3:122-139. Copyright © 2002, Academic sists longer than seizures, or even NCSE. Most patients
Press.
with NCSE have a prior history of seizures, but a
their patients, were implanted with electrodes, and after recently delineated entity of de novo NCSE in the
nine complex partial seizures over several days, followed elderly is being increasingly recognized.111 Aside from
by a 9-hour lucid interval, psychosis appeared. Recording medication or toxic screening of blood and urine, the sin-
showed frequent bitemporal, independent, epileptiform gle most helpful test is EEG, but interpretation may be
discharges over the mesial limbic structures, but without problematic. At one end of the spectrum, clear electro-
electrographic seizures.110 Logsdail and Toon suggest cri- graphic epileptiform activity in a rapid waxing and wan-
teria to distinguish postictal psychiatric disturbances and ing pattern suggests seizures, but certain metabolic and
other syndromes (Table II).90 particularly toxic encephalopathies may also have
sharply contoured morphologies on EEG, such as
Conclusion triphasic waves, which may strongly resemble—or
indeed be indistinguishable from—electrographic
Delirium and epilepsy may be difficult to differentiate, and seizures. In cases in which one of the entities is thought
there may be considerable overlap between the two states. to be present, there should be an immediate stopping of
One imitates the other because of the commonly fluctu- possible delirium-causing medications, an investigation
ating level of consciousness, abnormal behaviors, and sub- for underlying organ failure, a high index for seizures,
tle motor manifestations.ASE and CPSE can be mistaken and particularly nonconvulsive status with an EEG.
for delirium, encephalopathy, or psychiatric diseases (Table Incorrect or delayed diagnosis of either entity may
V).98 Seizures may present with ictal, interictal, or postic- increase morbidity and mortality. ❏

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Clinical research
Delirium y epilepsia Délire et épilepsie

El delirium (un estado de disfunción cerebral glo- Le délire (un état de dysfonctionnement cérébral
bal, usualmente reversible debido a causas tóxicas, global habituellement réversible, d’origine toxique,
metabólicas o infecciosas) y la epilepsia (una con- métabolique ou infectieuse) et l’épilepsie (un état
dición espontánea, recurrente de disfunción o exci- spontané récurrent de dysfonctionnement ou d’ex-
tación eléctrica paroxística) cada día se comprenden citation électrique paroxystique) sont de mieux en
mejor, por lo que resultan más fáciles de diagnosti- mieux compris et donc plus faciles à diagnostiquer et
car y de tratar. Las características clínicas del deli- à traiter. Le tableau clinique du délire est marqué
rium incluyen predominantemente cambios suba- essentiellement par des modifications subaiguës de
gudos de tipo cognitivo, en la conciencia reflexiva, la cognition, de la connaissance, et des niveaux d’ac-
en el nivel de actividad, trastornos de conducta, tivité, des troubles comportementaux, une obnubi-
obnubilación de conciencia y cambios del ciclo lation et des changements des rythmes veille-som-
sueño vigilia. En oposición, la epilepsia significa la meil. À l’opposé, l’épilepsie entraîne l’interruption
interrupción aguda del funcionamiento cerebral, a brutale de la fonction cérébrale, qui s’accompagne
menudo con actividad convulsiva, caídas y heridas. souvent de convulsions, chutes et blessures. Les
También son importantes los cuadros clínicos que pathologies pouvant associer des aspects propres à
pueden compartir características de ambas patolo- ces deux tableaux cliniques, comme les épilepsies
gías, como los estados epilépticos no convulsivos, sans convulsions, sont également importantes : la
en que la causa del trastorno cerebral es una acti- cause du trouble cérébral est une activité cérébrale
vidad eléctrica anormal y excesiva. En tales condi- électrique anormale et excessive. Dans ce cas, les
ciones, las manifestaciones clínicas pueden simular signes cliniques peuvent être semblables dans les
cuadros de delirium y confusión, y es significativa la états de délire et de confusion et l’absence de
ausencia de convulsiones clínicamente manifiestas. convulsions cliniquement manifestes est significative.
El electroencefalograma se mantiene como la L’électroencéphalogramme reste le test diagnostique
prueba diagnóstica de elección y resulta esencial de choix : il est indispensable pour différencier ces
para diferenciar entre las dos condiciones y adecuar deux pathologies, et donc spécifiquement adapter
los distintos tratamientos para el delirium y la epi- le traitement, soit au délire, soit à l’épilepsie. La
lepsia. La experimentación y las investigaciones en recherche et les investigations en cours sont essen-
curso son esenciales para una mejor comprensión tielles pour une meilleure compréhension des méca-
de los mecanismos cerebrales anormales que sub- nismes cérébraux anormaux sous-jacents au délire et
yacen al delirium y para desarrollar mejores herra- le développement de meilleurs outils de diagnostic
mientas para un diagnóstico objetivo. objectif.

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